Journal of Genetic Medicine

Korean Society of Medical Genetics and Genomics (대한의학유전학회)
권호 표지
DOI QR코드

DOI QR Code

Clinical application of chromosomal microarray for pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotype

  • Lee, Dongsook (Research Center of Fertility & Genetics, Hamchoon Women's Clinic) ;
  • Go, Sanghee (Research Center of Fertility & Genetics, Hamchoon Women's Clinic) ;
  • Na, Sohyun (Research Center of Fertility & Genetics, Hamchoon Women's Clinic) ;
  • Park, Surim (Research Center of Fertility & Genetics, Hamchoon Women's Clinic) ;
  • Ma, Jinyoung (Research Center of Fertility & Genetics, Hamchoon Women's Clinic) ;
  • Hwang, Doyeong (Research Center of Fertility & Genetics, Hamchoon Women's Clinic)
  • Received : 2020.05.24
  • Accepted : 2020.06.15
  • Published : 2020.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: To evaluate the additive value of prenatal chromosomal microarray analysis (CMA) in assessing increased nuchal translucency (NT) (≥3.5 mm) with normal karyotype and the possibility of detecting clinically significant genomic imbalance, based on specific indications. Materials and Methods: Invasive samples from 494 pregnancies with NT ≥3.5 mm, obtained from the Research Center of Fertility & Genetics of Hamchoon Women's Clinic between January 2019 and February 2020, were included in this study and CMA was performed in addition to a standard karyotype. Results: In total, 494 cases were subjected to both karyotype and CMA analyses. Among these, 199 cases of aneuploidy were excluded. CMA was performed on the remaining 295 cases (59.7%), which showed normal (231/295, 78.3%) or non-significant copy number variation (CNV), such as benign CNV or variants of uncertain clinical significance likely benign (53/295, 18.0%). Clinically significant CNVs were detected in 11 cases (11/295, 3.7%). Conclusion: Prenatal CMA resulted in a 3% to 4% higher CNV diagnosis rate in fetuses exhibiting increased NT (≥3.5 mm) without other ultrasound detected anomalies and normal karyotype. Therefore, we suggest using high resolution, non- targeting CMA to provide valuable additional information for prenatal diagnosis. Further, we recommend that a genetics specialist should be consulted to interpret the information appropriately and provide counseling and follow-up services after prenatal CMA.

Keywords

References

  1. Egloff M, Herve B, Quibel T, Jaillard S, Le Bouar G, Uguen K, et al. Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study. Ultrasound Obstet Gynecol 2018;52:715-21. https://doi.org/10.1002/uog.18928
  2. Maya I, Yacobson S, Kahana S, Yeshaya J, Tenne T, Agmon-Fishman I, et al. Cut-off value of nuchal translucency as indication for chromosomal microarray analysis. Ultrasound Obstet Gynecol 2017;50:332-5.
  3. Bornstein E, Berger S, Cheung SW, Maliszewski KT, Patel A, Pursley AN, et al. Universal prenatal chromosomal microarray analysis: additive value and clinical dilemmas in fetuses with a normal karyotype. Am J Perinatol 2017;34:340-8. https://doi.org/10.1055/s-0036-1586501
  4. Cicatiello R, Pignataro P, Izzo A, Mollo N, Pezone L, Maruotti GM, et al. Chromosomal microarray analysis versus karyotyping in fetuses with increased nuchal translucency. Med Sci (Basel) 2019;7:40.
  5. Armour CM, Dougan SD, Brock JA, Chari R, Chodirker BN, DeBie I, et al.; On-Behalf-Of the Canadian College of Medical Geneticists. Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada. J Med Genet 2018;55:215-21. https://doi.org/10.1136/jmedgenet-2017-105013
  6. Breman A, Pursley AN, Hixson P, Bi W, Ward P, Bacino CA, et al. Prenatal chromosomal microarray analysis in a diagnostic laboratory; experience with >1000 cases and review of the literature. Prenat Diagn 2012;32:351-61. https://doi.org/10.1002/pd.3861
  7. Stosic M, Levy B, Wapner R. The use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol Clin North Am 2018;45:55-68. https://doi.org/10.1016/j.ogc.2017.10.002
  8. Su L, Huang H, An G, Cai M, Wu X, Li Y, et al. Clinical application of chromosomal microarray analysis in fetuses with increased nuchal translucency and normal karyotype. Mol Genet Genomic Med 2019;7:e811.
  9. Zhao XR, Gao L, Wu Y, Wang YL. Application of chromosomal microarray in fetuses with increased nuchal translucency. J Matern Fetal Neonatal Med 2020;33:1749-54. https://doi.org/10.1080/14767058.2019.1569622
  10. South ST, Lee C, Lamb AN, Higgins AW, Kearney HM; Working Group for the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med 2013;15:901-9. https://doi.org/10.1038/gim.2013.129
  11. Lee D, Na S, Park S, Go S, Ma J, Yang S, et al. Clinical experience with multiplex ligation-dependent probe amplification for microdeletion syndromes in prenatal diagnosis: 7522 pregnant Korean women. Mol Cytogenet 2019;12:10. https://doi.org/10.1186/s13039-019-0422-8
  12. Leung TY, Au Yeung KC, Leung WC, Leung KY, Lo TK, To WWK, et al. Prenatal diagnosis of pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotyping using chromosomal microarray. Hong Kong Med J 2019;25 Suppl 5:30-2.
  13. Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, Scott DA, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 2010;47:332-41. https://doi.org/10.1136/jmg.2009.073015
  14. Chen CP, Chen CY, Chern SR, Wu PS, Chen SW, Lai ST, et al. Molecular cytogenetic characterization of a duplication of 15q24.2-q26.2 associated with anencephaly and neural tube defect. Taiwan J Obstet Gynecol 2017;56:550-3. https://doi.org/10.1016/j.tjog.2017.06.003
  15. Wat MJ, Shchelochkov OA, Holder AM, Breman AM, Dagli A, Bacino C, et al. Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia. Am J Med Genet A 2009;149A:1661-77. https://doi.org/10.1002/ajmg.a.32896
  16. Fernandez T, Morgan T, Davis N, Klin A, Morris A, Farhi A, et al. Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 2004;74:1286-93. https://doi.org/10.1086/421474
  17. Gamba BF, Zechi-Ceide RM, Kokitsu-Nakata NM, Vendramini-Pittoli S, Rosenberg C, Krepischi Santos AC, et al. Interstitial 1q21.1 microdeletion is associated with severe skeletal anomalies, dysmorphic face and moderate intellectual disability. Mol Syndromol 2016;7:344-8. https://doi.org/10.1159/000450971
  18. Burgess T, Brown NJ, Stark Z, Bruno DL, Oertel R, Chong B, et al. Characterization of core clinical phenotypes associated with recurrent proximal 15q25.2 microdeletions. Am J Med Genet A 2014;164A:77-86.
  19. Dharmadhikari AV, Kang SH, Szafranski P, Person RE, Sampath S, Prakash SK, et al. Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148. Hum Mol Genet 2012;21:3345-55. https://doi.org/10.1093/hmg/dds166
  20. Weise A, Mrasek K, Klein E, Mulatinho M, Llerena JC Jr, Hardekopf D, et al. Microdeletion and microduplication syndromes. J Histochem Cytochem 2012;60:346-58. https://doi.org/10.1369/0022155412440001
  21. Lal D, Trucks H, Moller RS, Hjalgrim H, Koeleman BP, de Kovel CG, et al.; EMINet Consortium; EPICURE Consortium. Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia 2013;54:265-71. https://doi.org/10.1111/epi.12084
  22. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a firsttier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86:749-64. https://doi.org/10.1016/j.ajhg.2010.04.006
  23. Burnside RD. 22q11.21 Deletion syndromes: a review of proximal, central, and distal deletions and their associated features. Cytogenet Genome Res 2015;146:89-99. https://doi.org/10.1159/000438708
  24. Huang LY, Pan M, Han J, Zhen L, Yang X, Li DZ. What would be missed in the first trimester if nuchal translucency measurement is replaced by cell free DNA foetal aneuploidy screening? J Obstet Gynaecol 2018;38:498-501. https://doi.org/10.1080/01443615.2017.1391755
  25. Lund IC, Christensen R, Petersen OB, Vogel I, Vestergaard EM. Chromosomal microarray in fetuses with increased nuchal translucency. Ultrasound Obstet Gynecol 2015;45:95-100. https://doi.org/10.1002/uog.14726